Vanadium(II)- and niobium(III)-induced, diastereoselective pinacol coupling of peptide aldehydes to give a C-2-symmetrical HIV protease inhibitor

Peptide aldehydes 15 a-c are prepared without epimerization from enantiomerically pure (S)-alpha-amino acids (Scheme 3), Reductive pinacol homocoupling of 15 a-c, induced by vanadium complex 11 or niobium complex 16 in refluxing THF, yields C-2-symmetrical (S,R,R,S)-configurated 6 a, 6 b and 2, respectively, with moderate to high stereoselectivity (Scheme 4), In a novel protocol for the preparation and utilization of THF solutions of 11, the isolation of air-sensitive intermediates can be avoided and the potent HIV protease inhibitor 2 prepared in enantio- and diastereomerically pure form on a kilogram scale without chromatographic purification. The (S,R,R,S) selectivity of the pinacol homocouplings is confirmed by means of an independent, stereochemically unequivocal synthesis of 6 a and 2 from D-mannitol 4 (Scheme 1).